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1.  Gene–Environment Interplay in Physical, Psychological, and Cognitive Domains in Mid to Late Adulthood: Is APOE a Variability Gene? 
Behavior genetics  2015;46(1):4-19.
Despite emerging interest in gene–environment interaction (GxE) effects, there is a dearth of studies evaluating its potential relevance apart from specific hypothesized environments and biometrical variance trends. Using a monozygotic within-pair approach, we evaluated evidence of G×E for body mass index (BMI), depressive symptoms, and cognition (verbal, spatial, attention, working memory, perceptual speed) in twin studies from four countries. We also evaluated whether APOE is a ‘variability gene’ across these measures and whether it partly represents the ‘G’ in G×E effects. In all three domains, G×E effects were pervasive across country and gender, with small-to-moderate effects. Age-cohort trends were generally stable for BMI and depressive symptoms; however, they were variable—with both increasing and decreasing age-cohort trends—for different cognitive measures. Results also suggested that APOE may represent a ‘variability gene’ for depressive symptoms and spatial reasoning, but not for BMI or other cognitive measures. Hence, additional genes are salient beyond APOE.
doi:10.1007/s10519-015-9761-3
PMCID: PMC4858319  PMID: 26538244
Gene–environment interaction; Twins; BMI; Depression; Cognitive performance; APOE; Variability gene
2.  Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994 
Jelenkovic, Aline | Hur, Yoon-Mi | Sund, Reijo | Yokoyama, Yoshie | Siribaddana, Sisira H | Hotopf, Matthew | Sumathipala, Athula | Rijsdijk, Fruhling | Tan, Qihua | Zhang, Dongfeng | Pang, Zengchang | Aaltonen, Sari | Heikkilä, Kauko | Öncel, Sevgi Y | Aliev, Fazil | Rebato, Esther | Tarnoki, Adam D | Tarnoki, David L | Christensen, Kaare | Skytthe, Axel | Kyvik, Kirsten O | Silberg, Judy L | Eaves, Lindon J | Maes, Hermine H | Cutler, Tessa L | Hopper, John L | Ordoñana, Juan R | Sánchez-Romera, Juan F | Colodro-Conde, Lucia | Cozen, Wendy | Hwang, Amie E | Mack, Thomas M | Sung, Joohon | Song, Yun-Mi | Yang, Sarah | Lee, Kayoung | Franz, Carol E | Kremen, William S | Lyons, Michael J | Busjahn, Andreas | Nelson, Tracy L | Whitfield, Keith E | Kandler, Christian | Jang, Kerry L | Gatz, Margaret | Butler, David A | Stazi, Maria A | Fagnani, Corrado | D'Ippolito, Cristina | Duncan, Glen E | Buchwald, Dedra | Derom, Catherine A | Vlietinck, Robert F | Loos, Ruth JF | Martin, Nicholas G | Medland, Sarah E | Montgomery, Grant W | Jeong, Hoe-Uk | Swan, Gary E | Krasnow, Ruth | Magnusson, Patrik KE | Pedersen, Nancy L | Dahl-Aslan, Anna K | McAdams, Tom A | Eley, Thalia C | Gregory, Alice M | Tynelius, Per | Baker, Laura A | Tuvblad, Catherine | Bayasgalan, Gombojav | Narandalai, Danshiitsoodol | Lichtenstein, Paul | Spector, Timothy D | Mangino, Massimo | Lachance, Genevieve | Bartels, Meike | van Beijsterveldt, Toos CEM | Willemsen, Gonneke | Burt, S Alexandra | Klump, Kelly L | Harris, Jennifer R | Brandt, Ingunn | Nilsen, Thomas Sevenius | Krueger, Robert F | McGue, Matt | Pahlen, Shandell | Corley, Robin P | Hjelmborg, Jacob v B | Goldberg, Jack H | Iwatani, Yoshinori | Watanabe, Mikio | Honda, Chika | Inui, Fujio | Rasmussen, Finn | Huibregtse, Brooke M | Boomsma, Dorret I | Sørensen, Thorkild I A | Kaprio, Jaakko | Silventoinen, Karri
eLife  null;5:e20320.
Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886–1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve.
DOI: http://dx.doi.org/10.7554/eLife.20320.001
doi:10.7554/eLife.20320
PMCID: PMC5156525  PMID: 27964777
height; twins; heritability; birth cohorts; CODATwins project; Human
3.  Leisure-Time Physical Activity and Academic Performance: Cross-Lagged Associations from Adolescence to Young Adulthood 
Scientific Reports  2016;6:39215.
Physical activity and academic performance are positively associated, but the direction of the association is poorly understood. This longitudinal study examined the direction and magnitude of the associations between leisure-time physical activity and academic performance throughout adolescence and young adulthood. The participants were Finnish twins (from 2,859 to 4,190 individuals/study wave) and their families. In a cross-lagged path model, higher academic performance at ages 12, 14 and 17 predicted higher leisure-time physical activity at subsequent time-points (standardized path coefficient at age 14: 0.07 (p < 0.001), age 17: 0.12 (p < 0.001) and age 24: 0.06 (p < 0.05)), whereas physical activity did not predict future academic performance. A cross-lagged model of co-twin differences suggested that academic performance and subsequent physical activity were not associated due to the environmental factors shared by co-twins. Our findings suggest that better academic performance in adolescence modestly predicts more frequent leisure-time physical activity in late adolescence and young adulthood.
doi:10.1038/srep39215
PMCID: PMC5156951  PMID: 27976699
4.  Branched-Chain Amino Acid Levels Are Related with Surrogates of Disturbed Lipid Metabolism among Older Men 
Aims/hypothesis
Existing studies suggest that decreased branched-chain amino acid (BCAA) catabolism and thus elevated levels in blood are associated with metabolic disturbances. Based on such information, we have developed a hypothesis how BCAA degradation mechanistically connects to tricarboxylic acid cycle, intramyocellular lipid storage, and oxidation, thus allowing more efficient mitochondrial energy production from lipids as well as providing better metabolic health. We analyzed whether data from aged Finnish men are in line with our mechanistic hypothesis linking BCAA catabolism and metabolic disturbances.
Methods
Older Finnish men enriched with individuals having been athletes in young adulthood (n = 593; mean age 72.6 ± 5.9 years) responded to questionnaires, participated in a clinical examination including assessment of body composition with bioimpedance and gave fasting blood samples for various analytes as well as participated in a 2-h 75 g oral glucose tolerance test. Metabolomics measurements from serum included BCAAs (isoleucine, leucine, and valine).
Results
Out of the 593 participants, 59 had previously known type 2 diabetes, further 67 had screen-detected type 2 diabetes, 127 impaired glucose tolerance, and 125 impaired fasting glucose, while 214 had normal glucose regulation and one had missing glucose tolerance information. There were group differences in all of the BCAA concentrations (p ≤ 0.005 for all BCAAs), such that those with normal glucose tolerance had the lowest and those with diabetes mellitus had the highest BCAA concentrations. All BCAA levels correlated positively with body fat percentage (r = 0.29–0.34, p < 0.0001 for all). Expected associations with high BCAA concentrations and unfavorable metabolic profile indicators from metabolomics analysis were found. Except for glucose concentrations, the associations were stronger with isoleucine and leucine than with valine.
Conclusion/interpretation
The findings provided further support for our hypothesis by strengthening the idea that the efficiency of BCAA catabolism may be mechanistically involved in the regulation of fat oxidation, thus affecting the levels of metabolic disease risk factors.
doi:10.3389/fmed.2016.00057
PMCID: PMC5122573  PMID: 27933294
branched-chain amino acids; metabolic disease; tricarboxylic acid cycle; lipid oxidation; mitochondria; energy metabolism
5.  Genome-wide association study identifies 74 loci associated with educational attainment 
Okbay, Aysu | Beauchamp, Jonathan P. | Fontana, Mark A. | Lee, James J. | Pers, Tune H. | Rietveld, Cornelius A. | Turley, Patrick | Chen, Guo-Bo | Emilsson, Valur | Meddens, S. Fleur W. | Oskarsson, Sven | Pickrell, Joseph K. | Thom, Kevin | Timshel, Pascal | de Vlaming, Ronald | Abdellaoui, Abdel | Ahluwalia, Tarunveer S. | Bacelis, Jonas | Baumbach, Clemens | Bjornsdottir, Gyda | Brandsma, Johannes H. | Concas, Maria Pina | Derringer, Jaime | Furlotte, Nicholas A. | Galesloot, Tessel E. | Girotto, Giorgia | Gupta, Richa | Hall, Leanne M. | Harris, Sarah E. | Hofer, Edith | Horikoshi, Momoko | Huffman, Jennifer E. | Kaasik, Kadri | Kalafati, Ioanna P. | Karlsson, Robert | Kong, Augustine | Lahti, Jari | van der Lee, Sven J. | de Leeuw, Christiaan | Lind, Penelope A. | Lindgren, Karl-Oskar | Liu, Tian | Mangino, Massimo | Marten, Jonathan | Mihailov, Evelin | Miller, Michael B. | van der Most, Peter J. | Oldmeadow, Christopher | Payton, Antony | Pervjakova, Natalia | Peyrot, Wouter J. | Qian, Yong | Raitakari, Olli | Rueedi, Rico | Salvi, Erika | Schmidt, Börge | Schraut, Katharina E. | Shi, Jianxin | Smith, Albert V. | Poot, Raymond A. | Pourcain, Beate | Teumer, Alexander | Thorleifsson, Gudmar | Verweij, Niek | Vuckovic, Dragana | Wellmann, Juergen | Westra, Harm-Jan | Yang, Jingyun | Zhao, Wei | Zhu, Zhihong | Alizadeh, Behrooz Z. | Amin, Najaf | Bakshi, Andrew | Baumeister, Sebastian E. | Biino, Ginevra | Bønnelykke, Klaus | Boyle, Patricia A. | Campbell, Harry | Cappuccio, Francesco P. | Davies, Gail | De Neve, Jan-Emmanuel | Deloukas, Panos | Demuth, Ilja | Ding, Jun | Eibich, Peter | Eisele, Lewin | Eklund, Niina | Evans68, David M. | Faul, Jessica D. | Feitosa, Mary F. | Forstner, Andreas J. | Gandin, Ilaria | Gunnarsson, Bjarni | Halldórsson, Bjarni V. | Harris, Tamara B. | Heath, Andrew C. | Hocking, Lynne J. | Holliday, Elizabeth G. | Homuth, Georg | Horan, Michael A. | Hottenga, Jouke-Jan | de Jager, Philip L. | Joshi, Peter K. | Jugessur, Astanand | Kaakinen, Marika A. | Kähönen, Mika | Kanoni, Stavroula | Keltigangas-Järvinen, Liisa | Kiemeney, Lambertus A.L.M. | Kolcic, Ivana | Koskinen, Seppo | Kraja, Aldi T. | Kroh, Martin | Kutalik, Zoltan | Latvala, Antti | Launer, Lenore J. | Lebreton, Maël P. | Levinson, Douglas F. | Lichtenstein, Paul | Lichtner, Peter | Liewald, David C.M. | Loukola, Anu | Madden, Pamela A. | Mägi, Reedik | Mäki-Opas, Tomi | Marioni, Riccardo E. | Marques-Vidal, Pedro | Meddens, Gerardus A. | McMahon, George | Meisinger, Christa | Meitinger, Thomas | Milaneschi, Yusplitri | Milani, Lili | Montgomery, Grant W. | Myhre, Ronny | Nelson, Christopher P. | Nyholt, Dale R. | Ollier, William E.R. | Palotie, Aarno | Paternoster, Lavinia | Pedersen, Nancy L. | Petrovic, Katja E. | Porteous, David J. | Räikkönen, Katri | Ring, Susan M. | Robino, Antonietta | Rostapshova, Olga | Rudan, Igor | Rustichini, Aldo | Salomaa, Veikko | Sanders, Alan R. | Sarin, Antti-Pekka | Schmidt, Helena | Scott, Rodney J. | Smith, Blair H. | Smith, Jennifer A. | Staessen, Jan A. | Steinhagen-Thiessen, Elisabeth | Strauch, Konstantin | Terracciano, Antonio | Tobin, Martin D. | Ulivi, Sheila | Vaccargiu, Simona | Quaye, Lydia | van Rooij, Frank J.A. | Venturini, Cristina | Vinkhuyzen, Anna A.E. | Völker, Uwe | Völzke, Henry | Vonk, Judith M. | Vozzi, Diego | Waage, Johannes | Ware, Erin B. | Willemsen, Gonneke | Attia, John R. | Bennett, David A. | Berger, Klaus | Bertram, Lars | Bisgaard, Hans | Boomsma, Dorret I. | Borecki, Ingrid B. | Bultmann, Ute | Chabris, Christopher F. | Cucca, Francesco | Cusi, Daniele | Deary, Ian J. | Dedoussis, George V. | van Duijn, Cornelia M. | Eriksson, Johan G. | Franke, Barbara | Franke, Lude | Gasparini, Paolo | Gejman, Pablo V. | Gieger, Christian | Grabe, Hans-Jörgen | Gratten, Jacob | Groenen, Patrick J.F. | Gudnason, Vilmundur | van der Harst, Pim | Hayward, Caroline | Hinds, David A. | Hoffmann, Wolfgang | Hyppönen, Elina | Iacono, William G. | Jacobsson, Bo | Järvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Kaprio, Jaakko | Kardia, Sharon L.R. | Lehtimäki, Terho | Lehrer, Steven F. | Magnusson, Patrik K.E. | Martin, Nicholas G. | McGue, Matt | Metspalu, Andres | Pendleton, Neil | Penninx, Brenda W.J.H. | Perola, Markus | Pirastu, Nicola | Pirastu, Mario | Polasek, Ozren | Posthuma, Danielle | Power, Christine | Province, Michael A. | Samani, Nilesh J. | Schlessinger, David | Schmidt, Reinhold | Sørensen, Thorkild I.A. | Spector, Tim D. | Stefansson, Kari | Thorsteinsdottir, Unnur | Thurik, A. Roy | Timpson, Nicholas J. | Tiemeier, Henning | Tung, Joyce Y. | Uitterlinden, André G. | Vitart, Veronique | Vollenweider, Peter | Weir, David R. | Wilson, James F. | Wright, Alan F. | Conley, Dalton C. | Krueger, Robert F. | Smith, George Davey | Hofman, Albert | Laibson, David I. | Medland, Sarah E. | Meyer, Michelle N. | Yang, Jian | Johannesson, Magnus | Visscher, Peter M. | Esko, Tõnu | Koellinger, Philipp D. | Cesarini, David | Benjamin, Daniel J.
Nature  2016;533(7604):539-542.
Summary
Educational attainment (EA) is strongly influenced by social and other environmental factors, but genetic factors are also estimated to account for at least 20% of the variation across individuals1. We report the results of a genome-wide association study (GWAS) for EA that extends our earlier discovery sample1,2 of 101,069 individuals to 293,723 individuals, and a replication in an independent sample of 111,349 individuals from the UK Biobank. We now identify 74 genome-wide significant loci associated with number of years of schooling completed. Single-nucleotide polymorphisms (SNPs) associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioral phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because EA is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric disease.
doi:10.1038/nature17671
PMCID: PMC4883595  PMID: 27225129
6.  Genetic variants associated with subjective well-being, depressive symptoms and neuroticism identified through genome-wide analyses 
Okbay, Aysu | Baselmans, Bart M L | De Neve, Jan-Emmanuel | Turley, Patrick | Nivard, Michel G | Fontana, Mark Alan | Meddens, S Fleur W | Linnér, Richard Karlsson | Rietveld, Cornelius A | Derringer, Jaime | Gratten, Jacob | Lee, James J | Liu, Jimmy Z | de Vlaming, Ronald | Ahluwalia, Tarunveer S | Buchwald, Jadwiga | Cavadino, Alana | Frazier-Wood, Alexis C | Davies, Gail | Furlotte, Nicholas A | Garfield, Victoria | Geisel, Marie Henrike | Gonzalez, Juan R | Haitjema, Saskia | Karlsson, Robert | van der Laan, Sander W | Ladwig, Karl-Heinz | Lahti, Jari | van der Lee, Sven J | Miller, Michael B | Lind, Penelope A | Liu, Tian | Matteson, Lindsay | Mihailov, Evelin | Minica, Camelia C | Nolte, Ilja M | Mook-Kanamori, Dennis O | van der Most, Peter J | Oldmeadow, Christopher | Qian, Yong | Raitakari, Olli | Rawal, Rajesh | Realo, Anu | Rueedi, Rico | Schmidt, Börge | Smith, Albert V | Stergiakouli, Evie | Tanaka, Toshiko | Taylor, Kent | Thorleifsson, Gudmar | Wedenoja, Juho | Wellmann, Juergen | Westra, Harm-Jan | Willems, Sara M | Zhao, Wei | Amin, Najaf | Bakshi, Andrew | Bergmann, Sven | Bjornsdottir, Gyda | Boyle, Patricia A | Cherney, Samantha | Cox, Simon R | Davis, Oliver S P | Ding, Jun | Direk, Nese | Eibich, Peter | Emeny, Rebecca T | Fatemifar, Ghazaleh | Faul, Jessica D | Ferrucci, Luigi | Forstner, Andreas J | Gieger, Christian | Gupta, Richa | Harris, Tamara B | Harris, Juliette M | Holliday, Elizabeth G | Hottenga, Jouke-Jan | De Jager, Philip L | Kaakinen, Marika A | Kajantie, Eero | Karhunen, Ville | Kolcic, Ivana | Kumari, Meena | Launer, Lenore J | Franke, Lude | Li-Gao, Ruifang | Liewald, David C | Koini, Marisa | Loukola, Anu | Marques-Vidal, Pedro | Montgomery, Grant W | Mosing, Miriam A | Paternoster, Lavinia | Pattie, Alison | Petrovic, Katja E | Pulkki-Råback, Laura | Quaye, Lydia | Räikkönen, Katri | Rudan, Igor | Scott, Rodney J | Smith, Jennifer A | Sutin, Angelina R | Trzaskowski, Maciej | Vinkhuyzen, Anna E | Yu, Lei | Zabaneh, Delilah | Attia, John R | Bennett, David A | Berger, Klaus | Bertram, Lars | Boomsma, Dorret I | Snieder, Harold | Chang, Shun-Chiao | Cucca, Francesco | Deary, Ian J | van Duijn, Cornelia M | Eriksson, Johan G | Bültmann, Ute | de Geus, Eco J C | Groenen, Patrick J F | Gudnason, Vilmundur | Hansen, Torben | Hartman, Catharine A | Haworth, Claire M A | Hayward, Caroline | Heath, Andrew C | Hinds, David A | Hyppönen, Elina | Iacono, William G | Järvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Kaprio, Jaakko | Kardia, Sharon L R | Keltikangas-Järvinen, Liisa | Kraft, Peter | Kubzansky, Laura D | Lehtimäki, Terho | Magnusson, Patrik K E | Martin, Nicholas G | McGue, Matt | Metspalu, Andres | Mills, Melinda | de Mutsert, Renée | Oldehinkel, Albertine J | Pasterkamp, Gerard | Pedersen, Nancy L | Plomin, Robert | Polasek, Ozren | Power, Christine | Rich, Stephen S | Rosendaal, Frits R | den Ruijter, Hester M | Schlessinger, David | Schmidt, Helena | Svento, Rauli | Schmidt, Reinhold | Alizadeh, Behrooz Z | Sørensen, Thorkild I A | Spector, Tim D | Starr, John M | Stefansson, Kari | Steptoe, Andrew | Terracciano, Antonio | Thorsteinsdottir, Unnur | Thurik, A Roy | Timpson, Nicholas J | Tiemeier, Henning | Uitterlinden, André G | Vollenweider, Peter | Wagner, Gert G | Weir, David R | Yang, Jian | Conley, Dalton C | Smith, George Davey | Hofman, Albert | Johannesson, Magnus | Laibson, David I | Medland, Sarah E | Meyer, Michelle N | Pickrell, Joseph K | Esko, Tõnu | Krueger, Robert F | Beauchamp, Jonathan P | Koellinger, Philipp D | Benjamin, Daniel J | Bartels, Meike | Cesarini, David
Nature genetics  2016;48(6):624-633.
We conducted genome-wide association studies of three phenotypes: subjective well-being (N = 298,420), depressive symptoms (N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with subjective well-being, two with depressive symptoms, and eleven with neuroticism, including two inversion polymorphisms. The two depressive symptoms loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings, and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are strongly enriched for association.
doi:10.1038/ng.3552
PMCID: PMC4884152  PMID: 27089181
7.  Metabolic signatures of birthweight in 18 288 adolescents and adults 
Background: Lower birthweight is associated with increased susceptibility to cardiometabolic diseases in adulthood, but the underlying molecular pathways are incompletely understood. We examined associations of birthweight with a comprehensive metabolic profile measured in adolescents and adults.
Methods: High-throughput nuclear magnetic resonance metabolomics and biochemical assays were used to quantify 87 circulating metabolic measures in seven cohorts from Finland and the UK, comprising altogether 18 288 individuals (mean age 26 years, range 15–75). Metabolic associations with birthweight were assessed by linear regression models adjusted for sex, gestational age and age at blood sampling. The metabolic associations with birthweight were compared with the corresponding associations with adult body mass index (BMI).
Results: Lower birthweight adjusted for gestational age was adversely associated with cardiometabolic biomarkers, including lipoprotein subclasses, fatty acids, amino acids and markers of inflammation and impaired liver function (P < 0.0015 for 46 measures). Associations were consistent across cohorts with different ages at metabolic profiling, but the magnitudes were weak. The pattern of metabolic deviations associated with lower birthweight resembled the metabolic signature of higher adult BMI (R2 = 0.77) assessed at the same time as the metabolic profiling. The resemblance indicated that 1 kg lower birthweight is associated with similar metabolic aberrations as caused by 0.92 units higher BMI in adulthood.
Conclusions: Lower birthweight adjusted for gestational age is associated with adverse biomarker aberrations across multiple metabolic pathways. Coherent metabolic signatures between lower birthweight and higher adult adiposity suggest that shared molecular pathways may potentially underpin the metabolic deviations. However, the magnitudes of metabolic associations with birthweight are modest in comparison to the effects of adiposity, implying that birthweight is only a weak indicator of the metabolic risk profile in adulthood.
doi:10.1093/ije/dyw255
PMCID: PMC5100627  PMID: 27892411
Fetal programming; metabolic signatures; metabolomics; adiposity; fatty acids; amino acids
8.  Role of the Neuregulin Signaling Pathway in Nicotine Dependence and Co-morbid Disorders 
Smoking is currently the leading cause of preventable death in the United States and is responsible for over four million deaths annually worldwide. Therefore, there is a vast clinical unmet need with regards to therapeutics targeting smoking cessation. This is even more apparent when examining smokers co-morbid with psychiatric illness, as rates of smoking in this population are ~4× higher than in the general population.
Examining common genetic and molecular signaling pathways impinging upon both smoking behavior and psychiatric illness will lead to a better understanding of co-morbid disorders and potential development of novel therapeutics. Studies have implicated the Neuregulin Signaling Pathway in the pathophysiology of a number of psychiatric illnesses. Additionally, recent studies have also shown an association between the Neuregulin Signaling Pathway and smoking behaviors. This review outlines basic mechanisms of the Neuregulin Signaling Pathway and how it may be exploited for precision medicine approaches in treating nicotine dependence and mental illness.
doi:10.1016/bs.irn.2015.07.006
PMCID: PMC5094186  PMID: 26472527
9.  Genetic variants associated with subjective well-being, depressive symptoms and neuroticism identified through genome-wide analyses 
Okbay, Aysu | Baselmans, Bart M.L. | De Neve, Jan-Emmanuel | Turley, Patrick | Nivard, Michel G. | Fontana, Mark Alan | Meddens, S. Fleur W. | Linnér, Richard Karlsson | Rietveld, Cornelius A. | Derringer, Jaime | Gratten, Jacob | Lee, James J. | Liu, Jimmy Z. | de Vlaming, Ronald | Ahluwalia, Tarunveer S. | Buchwald, Jadwiga | Cavadino, Alana | Frazier-Wood, Alexis C. | Furlotte, Nicholas A. | Garfield, Victoria | Geisel, Marie Henrike | Gonzalez, Juan R. | Haitjema, Saskia | Karlsson, Robert | van der Laan, Sander W. | Ladwig, Karl-Heinz | Lahti, Jari | van der Lee, Sven J. | Lind, Penelope A. | Liu, Tian | Matteson, Lindsay | Mihailov, Evelin | Miller, Michael B. | Minica, Camelia C. | Nolte, Ilja M. | Mook-Kanamori, Dennis | van der Most, Peter J. | Oldmeadow, Christopher | Qian, Yong | Raitakari, Olli | Rawal, Rajesh | Realo, Anu | Rueedi, Rico | Schmidt, Börge | Smith, Albert V. | Stergiakouli, Evie | Tanaka, Toshiko | Taylor, Kent | Wedenoja, Juho | Wellmann, Juergen | Westra, Harm-Jan | Willems, Sara M. | Zhao, Wei | Amin, Najaf | Bakshi, Andrew | Boyle, Patricia A. | Cherney, Samantha | Cox, Simon R. | Davies, Gail | Davis, Oliver S.P. | Ding, Jun | Direk, Nese | Eibich, Peter | Emeny, Rebecca T. | Fatemifar, Ghazaleh | Faul, Jessica D. | Ferrucci, Luigi | Forstner, Andreas | Gieger, Christian | Gupta, Richa | Harris, Tamara B. | Harris, Juliette M. | Holliday, Elizabeth G. | Hottenga, Jouke-Jan | De Jager, Philip L. | Kaakinen, Marika A. | Kajantie, Eero | Karhunen, Ville | Kolcic, Ivana | Kumari, Meena | Launer, Lenore J. | Franke, Lude | Li-Gao, Ruifang | Koini, Marisa | Loukola, Anu | Marques-Vidal, Pedro | Montgomery, Grant W. | Mosing, Miriam A. | Paternoster, Lavinia | Pattie, Alison | Petrovic, Katja E. | Pulkki-Råback, Laura | Quaye, Lydia | Räikkönen, Katri | Rudan, Igor | Scott, Rodney J. | Smith, Jennifer A. | Sutin, Angelina R. | Trzaskowski, Maciej | Vinkhuyzen, Anna E. | Yu, Lei | Zabaneh, Delilah | Attia, John R. | Bennett, David A. | Berger, Klaus | Bertram, Lars | Boomsma, Dorret I. | Snieder, Harold | Chang, Shun-Chiao | Cucca, Francesco | Deary, Ian J. | van Duijn, Cornelia M. | Eriksson, Johan G. | Bültmann, Ute | de Geus, Eco J.C. | Groenen, Patrick J.F. | Gudnason, Vilmundur | Hansen, Torben | Hartman, Catharine A. | Haworth, Claire M.A. | Hayward, Caroline | Heath, Andrew C. | Hinds, David A. | Hyppönen, Elina | Iacono, William G. | Järvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Kaprio, Jaakko | Kardia, Sharon L.R. | Keltikangas-Järvinen, Liisa | Kraft, Peter | Kubzansky, Laura D. | Lehtimäki, Terho | Magnusson, Patrik K.E. | Martin, Nicholas G. | McGue, Matt | Metspalu, Andres | Mills, Melinda | de Mutsert, Renée | Oldehinkel, Albertine J. | Pasterkamp, Gerard | Pedersen, Nancy L. | Plomin, Robert | Polasek, Ozren | Power, Christine | Rich, Stephen S. | Rosendaal, Frits R. | den Ruijter, Hester M. | Schlessinger, David | Schmidt, Helena | Svento, Rauli | Schmidt, Reinhold | Alizadeh, Behrooz Z. | Sørensen, Thorkild I.A. | Spector, Tim D. | Steptoe, Andrew | Terracciano, Antonio | Thurik, A. Roy | Timpson, Nicholas J. | Tiemeier, Henning | Uitterlinden, André G. | Vollenweider, Peter | Wagner, Gert G. | Weir, David R. | Yang, Jian | Conley, Dalton C. | Smith, George Davey | Hofman, Albert | Johannesson, Magnus | Laibson, David I. | Medland, Sarah E. | Meyer, Michelle N. | Pickrell, Joseph K. | Esko, Tõnu | Krueger, Robert F. | Beauchamp, Jonathan P. | Koellinger, Philipp D. | Benjamin, Daniel J. | Bartels, Meike | Cesarini, David
Nature genetics  2016;48(6):624-633.
We conducted genome-wide association studies of three phenotypes: subjective well-being (N = 298,420), depressive symptoms (N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with subjective well-being, two with depressive symptoms, and eleven with neuroticism, including two inversion polymorphisms. The two depressive symptoms loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ̂| ≈ 0.8) strengthen the overall credibility of the findings, and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are strongly enriched for association.
doi:10.1038/ng.3552
PMCID: PMC4884152  PMID: 27089181
10.  MOTOR DEVELOPMENT AND PHYSICAL ACTIVITY: A LONGITUDINAL DISCORDANT TWIN-PAIR STUDY 
Introduction
Previous longitudinal research suggests that motor proficiency in early life predicts physical activity in adulthood. Familial effects including genetic and environmental factors could explain the association, but no long-term follow-up studies have taken into account potential confounding by genetic and social family background. The present twin study investigated whether childhood motor skill development is associated with leisure-time physical activity levels in adulthood independent of family background.
Methods
Altogether, 1 550 twin pairs from the FinnTwin12 study and 1 752 twin pairs from the FinnTwin16 study were included in the analysis. Childhood motor development was assessed by the parents’ report of whether one of the co-twins had been ahead of the other in different indicators of motor skill development in childhood. Leisure-time physical activity (MET hours/day) was self-reported by the twins in young adulthood and adulthood. Statistical analyses included conditional and ordinary linear regression models within twin pairs.
Results
Using all activity-discordant twin pairs, the within-pair difference in a sum score of motor development in childhood predicted the within-pair difference in the leisure-time physical activity level in young adulthood (p<0.001). Within specific motor development indicators, learning to stand unaided earlier in infancy predicted higher leisure-time MET values in young adulthood statistically significantly in both samples (FinnTwin12 p=0.02, FinnTwin16 p=0.001) and also in the pooled dataset of the FinnTwin12 and FinnTwin16 studies (p<0.001). Having been more agile than the co-twin as a child predicted higher leisure-time MET values up to adulthood (p=0.03).
Conclusions
More advanced childhood motor development is associated with higher leisure-time MET values in young adulthood at least partly independent of family background, in both men and women.
doi:10.1249/MSS.0000000000000650
PMCID: PMC4576714  PMID: 26378945
ADOLESCENCE; EXERCISE; MOTOR SKILLS; PHYSICAL ACTIVITY; TWINS
11.  Molecular mechanisms underlying variations in lung function: a systems genetics analysis 
The Lancet. Respiratory medicine  2015;3(10):782-795.
Summary
Background
Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48 201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs.
Methods
The SpiroMeta-CHARGE GWAS results were integrated with lung eQTLs to map eSNPs and the genes and pathways underlying the associations in lung tissue. For comparison, a similar analysis was done in peripheral blood. The lung mRNA expression levels of the eSNP-regulated genes were tested for associations with lung function measures in 727 individuals. Additional analyses identified the pleiotropic effects of eSNPs from the published GWAS catalogue, and mapped enrichment in regulatory regions from the ENCODE project. Finally, the Connectivity Map database was used to identify potential therapeutics in silico that could reverse the COPD lung tissue gene signature.
Findings
SNPs associated with lung function measures were more likely to be eQTLs and vice versa. The integration mapped the specific genes underlying the GWAS signals in lung tissue. The eSNP-regulated genes were enriched for developmental and inflammatory pathways; by comparison, SNPs associated with lung function that were eQTLs in blood, but not in lung, were only involved in inflammatory pathways. Lung function eSNPs were enriched for regulatory elements and were over-represented among genes showing differential expression during fetal lung development. An mRNA gene expression signature for COPD was identified in lung tissue and compared with the Connectivity Map. This in-silico drug repurposing approach suggested several compounds that reverse the COPD gene expression signature, including a nicotine receptor antagonist. These findings represent novel therapeutic pathways for COPD.
Interpretation
The system genetics approach identified lung tissue genes driving the variation in lung function and susceptibility to COPD. The identification of these genes and the pathways in which they are enriched is essential to understand the pathophysiology of airway obstruction and to identify novel therapeutic targets and biomarkers for COPD, including drugs that reverse the COPD gene signature in silico.
Funding
The research reported in this article was not specifically funded by any agency. See Acknowledgments for a full list of funders of the lung eQTL study and the Spiro-Meta CHARGE GWAS.
doi:10.1016/S2213-2600(15)00380-X
PMCID: PMC5021067  PMID: 26404118
12.  Middle age self-report risk score predicts cognitive functioning and dementia in 20–40 years 
Introduction
On the basis of the proxy measures of cognitive reserve, we created a middle age self-report risk score for early prediction of dementia.
Methods
We used a longitudinal population-based study of 2602 individuals with a replication sample (N = 1011). Risk score at a mean age of 47 years was based on questions on educational and occupational attainments. Cognitive status at a mean age of 74 was determined via two validated telephone instruments.
Results
The prevalence of dementia was 10% after a mean follow-up of 28 years. Risk score was a good predictor of dementia: area under the curve = 0.77 (95% confidence interval, 0.74–0.80). The risk of dementia decreased as a function of risk score from 36% to 0%. The risk score was significantly associated with cognition after a mean follow-up of 39 years in the replication sample.
Discussion
Self-report risk score predicted cognitive functioning and dementia risk 20–40 years later.
Highlights
•We created a middle age self-report risk score that predicts dementia in 20–40 years.•Risk score consisted of questions on educational and occupational attainments.•These measures are considered as proxies of cognitive reserve.•Risk score is easily acquired low-cost tool for early identification of dementia risk.•Educational and occupational attainments build cognitive reserve against dementia.
doi:10.1016/j.dadm.2016.08.003
PMCID: PMC5061466  PMID: 27752535
Education; Early identification; Cognitive reserve; Dementia; Middle age; Occupation; Risk score; Twins
13.  An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation 
Genome Biology  2016;17(1):176.
Background
Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated.
Results
We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease.
Conclusions
This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-016-1041-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-016-1041-x
PMCID: PMC5004279  PMID: 27572077
Schizophrenia; DNA methylation; Epigenetics; Genetics; Polygenic risk score (PRS); Genome-wide association study (GWAS); Epigenome-wide association study (EWAS)
14.  Association between education and future leisure-time physical inactivity: a study of Finnish twins over a 35-year follow-up 
BMC Public Health  2016;16:720.
Background
Education is associated with health related lifestyle choices including leisure-time physical inactivity. However, the longitudinal associations between education and inactivity merit further studies. We investigated the association between education and leisure-time physical inactivity over a 35-year follow-up with four time points controlling for multiple covariates including familial confounding.
Methods
This study of the population-based Finnish Twin Cohort consisted of 5254 twin individuals born in 1945–1957 (59 % women), of which 1604 were complete same-sexed twin pairs. Data on leisure-time physical activity and multiple covariates was available from four surveys conducted in 1975, 1981, 1990 and 2011 (response rates 72 to 89 %). The association between years of education and leisure-time physical inactivity (<1.5 metabolic equivalent hours/day) was first analysed for each survey. Then, the role of education was investigated for 15-year and 35-year inactivity periods in the longitudinal analyses. The co-twin control design was used to analyse the potential familial confounding of the effects. All analyses were conducted with and without multiple covariates. Odds Ratios (OR) with 95 % Confidence Intervals (CI) were calculated using logistic and conditional (fixed-effects) regression models.
Results
Each additional year of education was associated with less inactivity (OR 0.94 to 0.95, 95 % CI 0.92, 0.99) in the cross-sectional age- and sex-adjusted analyses. The associations of education with inactivity in the 15- and 35-year follow-ups showed a similar trend: OR 0.97 (95 % CI 0.93, 1.00) and OR 0.94 (95 % CI 0.91, 0.98), respectively. In all co-twin control analyses, each year of higher education was associated with a reduced likelihood of inactivity suggesting direct effect (i.e. independent from familial confounding) of education on inactivity. However, the point estimates were lower than in the individual-level analyses. Adjustment for multiple covariates did not change these associations.
Conclusions
Higher education is associated with lower odds of leisure-time physical inactivity during the three-decade follow-up. The association was found after adjusting for several confounders, including familial factors. Hence, the results point to the conclusion that education has an independent role in the development of long-term physical inactivity and tailored efforts to promote physical activity among lower educated people would be needed throughout adulthood.
doi:10.1186/s12889-016-3410-5
PMCID: PMC4973543  PMID: 27492437
Adult; Behavioral genetics; Cohort studies; Educational status; Exercise; Follow-Up studies; Twins
15.  Nicotine Metabolite Ratio (3-hydroxycotinine/cotinine) in Plasma and Urine by Different Analytical Methods and Laboratories: Implications for Clinical Implementation 
Background
The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3′-hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers.
Methods
Plasma (n=35) and urine (n=35) samples were sent to eight different laboratories, which employed similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland-Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods.
Results
Measures of plasma NMR were in strong agreement between methods according to Bland-Altman analysis (ratios 0.82–1.16) and were highly correlated (all Pearson r>0.96, P<0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62–1.71) and less strongly correlated (Pearson r values of 0.66–0.98, P<0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than in urine, as was observed for NMR.
Conclusions
Plasma is a very reliable biological source for the determination of NMR, robust to differences in these analytical protocols or assessment site.
Impact
Together this indicates a reduced need for differential interpretation of plasma NMR results based on the approach used, allowing for direct comparison of different studies.
doi:10.1158/1055-9965.EPI-14-1381
PMCID: PMC4526326  PMID: 26014804
NMR; CYP2A6; nicotine; smoking; chromatography
16.  Intergenerational Continuity in Parents’ and Adolescents’ Externalizing Problems: The Role of Life Events and their Interaction with GABRA2 
Journal of abnormal psychology  2015;124(3):709-728.
We examine whether parental externalizing behavior has an indirect effect on adolescent externalizing behavior via elevations in life events, and whether this indirect effect is further qualified by an interaction between life events and adolescents’ GABRA2 genotype (rs279871). We use data from two samples: the Child Development Project [CDP] (n = 324) and FinnTwin12 (n = 802). In CDP, repeated measures of life events, mother-reported adolescent externalizing, and teacher-reported adolescent externalizing were used. In FinnTwin12, life events and externalizing were assessed at age 14. Parental externalizing was indexed by measures of antisocial behavior and alcohol problems or alcohol dependence symptoms in both samples. In CDP, parental externalizing was associated with more life events, and the association between life events and subsequent adolescent externalizing varied as a function of GABRA2 genotype (p ≤ 0.05). The association between life events and subsequent adolescent externalizing was stronger for adolescents with 0 copies of the G minor allele (MA) compared to those with 1 or 2 copies of the MA. Parallel moderation trends were observed in FinnTwin12 (p ≤ 0.11). The discussion focuses on how the strength of intergenerational pathways for externalizing psychopathology may differ as a function of adolescent-level individual differences.
doi:10.1037/abn0000066
PMCID: PMC4573794  PMID: 26075969
externalizing; GABRA2; gene-environment interaction; life events; intergenerational continuity
17.  Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer 
British Journal of Cancer  2016;115(2):266-272.
Background:
Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC.
Methods:
We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls.
Results:
In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02–1.49, P=0.033), 1.59 (95% CI: 1.08–2.34, P=0.019) and 1.07 (95% CI: 1.03–1.13, P=0.018), respectively. There was no evidence for association between birth weight and CRC (OR=1.22, 95% CI: 0.89–1.67, P=0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10–1.44, P=7.7 × 10−4) and 1.40 (95% CI: 1.14–1.72, P=1.2 × 10−3), respectively.
Conclusions:
These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity.
doi:10.1038/bjc.2016.188
PMCID: PMC4947703  PMID: 27336604
Mendelian randomisation; adiposity; colorectal cancer
18.  Smoking status and abdominal obesity among normal- and overweight/obese adults: Population-based FINRISK study 
Preventive Medicine Reports  2016;4:324-330.
Several studies have reported direct associations of smoking with body mass index (BMI) and abdominal obesity. However, the interplay between them is poorly understood. Our first aim was to investigate the interaction between smoking status and BMI on abdominal obesity (waist circumference, WC). Our second aim was to examine how the association of smoking status with WC varies among normal and overweight/obese men and women. We examined 5833 participants from the National FINRISK 2007 Study. The interactions between smoking and BMI on WC were analyzed. Participants were categorized into eight groups according to BMI (normal weight vs. overweight/obese) and smoking status (never smoker, ex-smoker, occasional/light/moderate daily smoker, heavy daily smoker). The associations between each BMI/smoking status -group and WC were analyzed by multiple regressions, the normal-weight never smokers as the reference group. The smoking status by BMI-interaction on WC was significant for women, but not for men. Among the overweight/obese women, ex-smokers (β = 2.73; 1.99, 3.46) and heavy daily smokers (β = 4.90; 3.35, 6.44) had the highest estimates for WC when adjusted for age, BMI, alcohol consumption and physical activity. In comparison to never smoking overweight/obese women, the β-coefficients of ex-smokers and heavy daily smokers were significantly higher. Among men and normal weight women the β -coefficients did not significantly differ by smoking status. An interaction between smoking status and BMI on abdominal obesity was observed in women: overweight/obese heavy daily smokers were particularly vulnerable for abdominal obesity. This risk group should be targeted for cardiovascular disease prevention.
Highlights
•There was a smoking status by BMI-interaction on abdominal obesity (AO) in women.•In overweight/obese women, heavy daily smokers were the most vulnerable for AO.•Among overweight/obese women, also ex-smokers had elevated AO.•Risk for AO due to smoking and overweight should be noted in clinical practice.•Smoking cessation interventions should also address post-cessation weight gain.
doi:10.1016/j.pmedr.2016.07.003
PMCID: PMC4959936  PMID: 27486563
Abdominal obesity; Body mass index; Smoking; Waist circumference
19.  Genetic and environmental influences on height from infancy to early adulthood: An individual-based pooled analysis of 45 twin cohorts 
Jelenkovic, Aline | Sund, Reijo | Hur, Yoon-Mi | Yokoyama, Yoshie | Hjelmborg, Jacob v. B. | Möller, Sören | Honda, Chika | Magnusson, Patrik K. E. | Pedersen, Nancy L. | Ooki, Syuichi | Aaltonen, Sari | Stazi, Maria A. | Fagnani, Corrado | D’Ippolito, Cristina | Freitas, Duarte L. | Maia, José Antonio | Ji, Fuling | Ning, Feng | Pang, Zengchang | Rebato, Esther | Busjahn, Andreas | Kandler, Christian | Saudino, Kimberly J. | Jang, Kerry L. | Cozen, Wendy | Hwang, Amie E. | Mack, Thomas M. | Gao, Wenjing | Yu, Canqing | Li, Liming | Corley, Robin P. | Huibregtse, Brooke M. | Derom, Catherine A. | Vlietinck, Robert F. | Loos, Ruth J. F. | Heikkilä, Kauko | Wardle, Jane | Llewellyn, Clare H. | Fisher, Abigail | McAdams, Tom A. | Eley, Thalia C. | Gregory, Alice M. | He, Mingguang | Ding, Xiaohu | Bjerregaard-Andersen, Morten | Beck-Nielsen, Henning | Sodemann, Morten | Tarnoki, Adam D. | Tarnoki, David L. | Knafo-Noam, Ariel | Mankuta, David | Abramson, Lior | Burt, S. Alexandra | Klump, Kelly L. | Silberg, Judy L. | Eaves, Lindon J. | Maes, Hermine H. | Krueger, Robert F. | McGue, Matt | Pahlen, Shandell | Gatz, Margaret | Butler, David A. | Bartels, Meike | van Beijsterveldt, Toos C. E. M. | Craig, Jeffrey M. | Saffery, Richard | Dubois, Lise | Boivin, Michel | Brendgen, Mara | Dionne, Ginette | Vitaro, Frank | Martin, Nicholas G. | Medland, Sarah E. | Montgomery, Grant W. | Swan, Gary E. | Krasnow, Ruth | Tynelius, Per | Lichtenstein, Paul | Haworth, Claire M. A. | Plomin, Robert | Bayasgalan, Gombojav | Narandalai, Danshiitsoodol | Harden, K. Paige | Tucker-Drob, Elliot M. | Spector, Timothy | Mangino, Massimo | Lachance, Genevieve | Baker, Laura A. | Tuvblad, Catherine | Duncan, Glen E. | Buchwald, Dedra | Willemsen, Gonneke | Skytthe, Axel | Kyvik, Kirsten O. | Christensen, Kaare | Öncel, Sevgi Y. | Aliev, Fazil | Rasmussen, Finn | Goldberg, Jack H. | Sørensen, Thorkild I. A. | Boomsma, Dorret I. | Kaprio, Jaakko | Silventoinen, Karri
Scientific Reports  2016;6:28496.
Height variation is known to be determined by both genetic and environmental factors, but a systematic description of how their influences differ by sex, age and global regions is lacking. We conducted an individual-based pooled analysis of 45 twin cohorts from 20 countries, including 180,520 paired measurements at ages 1–19 years. The proportion of height variation explained by shared environmental factors was greatest in early childhood, but these effects remained present until early adulthood. Accordingly, the relative genetic contribution increased with age and was greatest in adolescence (up to 0.83 in boys and 0.76 in girls). Comparing geographic-cultural regions (Europe, North-America and Australia, and East-Asia), genetic variance was greatest in North-America and Australia and lowest in East-Asia, but the relative proportion of genetic variation was roughly similar across these regions. Our findings provide further insights into height variation during childhood and adolescence in populations representing different ethnicities and exposed to different environments.
doi:10.1038/srep28496
PMCID: PMC4917845  PMID: 27333805
20.  Cohort Profile: The National Academy of Sciences-National Research Council Twin Registry (NAS-NRC Twin Registry) 
The National Academy of Sciences-National Research Council Twin Registry (NAS-NRC Twin Registry) is a comprehensive registry of White male twin pairs born in the USA between 1917 and 1927, both of the twins having served in the military. The purpose was medical research and ultimately improved clinical care. The cohort was assembled in the early 1960s with identification of approximately 16 000 twin pairs, review of service records, a brief mailed questionnaire assessing zygosity, and a health survey largely comparable to questionnaires used at that time with Scandinavian twin registries. Subsequent large-scale data collection occurred in 1974, 1985 and 1998, repeating the health survey and including information on education, employment history and earnings. Self-reported data have been supplemented with mortality, disability and medical data through record linkage. Potential collaborators should access the study website [http://www.iom.edu/Activities/Veterans/TwinsStudy.aspx] or e-mail the Medical Follow-up Agency at [Twins@nas.edu]. Questionnaire data are being prepared for future archiving with the National Archive of Computerized Data on Aging (NACDA) at the Inter-University Consortium for Political and Social Research (ICPSR), University of Michigan, MI.
doi:10.1093/ije/dyu181
PMCID: PMC4521123  PMID: 25183748
21.  Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis 
The American journal of psychiatry  2015;172(6):543-552.
Objective
The genetic component of alcohol use disorder is substantial, but monozygotic twin discordance indicates a role for nonheritable differences that could be mediated by epigenetics. Despite growing evidence associating epigenetics and psychiatric disorders, it is unclear how epigenetics, particularly DNA methylation, relate to brain function and behavior, including drinking behavior.
Method
The authors carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions. After validation, the authors characterized these differentially methylated regions using personality trait assessment and functional MRI in a sample of 499 adolescents.
Results
Hypermethylation in the 3′-protein-phosphatase-1G (PPM1G) gene locus was associated with alcohol use disorder. The authors found association of PPM1G hypermethylation with early escalation of alcohol use and increased impulsiveness. They also observed association of PPM1G hypermethylation with increased blood-oxygen-level-dependent response in the right subthalamic nucleus during an impulsiveness task.
Conclusions
Overall, the authors provide first evidence for an epigenetic marker associated with alcohol consumption and its underlying neurobehavioral phenotype.
doi:10.1176/appi.ajp.2014.14030382
PMCID: PMC4827248  PMID: 25982659
22.  Effect of Smoking on Blood Pressure and Resting Heart Rate: A Mendelian Randomisation Meta-Analysis in the CARTA Consortium 
Background
Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood.
Methods and Results
Data on 141,317 participants (62,666 never, 40,669 former, 37,982 current smokers) from 23 population-based studies were included in observational and Mendelian randomisation (MR) meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure (SBP, DBP), hypertension, and resting heart rate. For the MR analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower SBP, DBP, and lower hypertension risk, but with higher resting heart rate. In observational analyses amongst current smokers, one cigarette/day higher level of smoking heaviness was associated with higher (0.21 beats/minute; 95% CI 0.19; 0.24) resting heart rate, and slightly higher DBP (0.05 mmHg; 95% CI 0.02; 0.08) and SBP (0.08 mmHg; 95% CI 0.03; 0.13). However, in MR analyses amongst current smokers, while each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 beats/minute/allele; 95% CI 0.18; 0.54), there was no strong association with DBP, SBP, or hypertension. This would suggest a 7 beats/minute higher heart rate in those who smoke 20 cigarettes/day.
Conclusions
This MR meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.
doi:10.1161/CIRCGENETICS.115.001225
PMCID: PMC4684098  PMID: 26538566
blood pressure; hypertension; Mendelian randomization; heart rate; smoking
23.  Genetic Relationship between Schizophrenia and Nicotine Dependence 
Scientific Reports  2016;6:25671.
It is well known that most schizophrenia patients smoke cigarettes. There are different hypotheses postulating the underlying mechanisms of this comorbidity. We used summary statistics from large meta-analyses of plasma cotinine concentration (COT), Fagerström test for nicotine dependence (FTND) and schizophrenia to examine the genetic relationship between these traits. We found that schizophrenia risk scores calculated at P-value thresholds of 5 × 10−3 and larger predicted FTND and cigarettes smoked per day (CPD), suggesting that genes most significantly associated with schizophrenia were not associated with FTND/CPD, consistent with the self-medication hypothesis. The COT risk scores predicted schizophrenia diagnosis at P-values of 5 × 10−3 and smaller, implying that genes most significantly associated with COT were associated with schizophrenia. These results implicated that schizophrenia and FTND/CPD/COT shared some genetic liability. Based on this shared liability, we identified multiple long non-coding RNAs and RNA binding protein genes (DA376252, BX089737, LOC101927273, LINC01029, LOC101928622, HY157071, DA902558, RBFOX1 and TINCR), protein modification genes (MANBA, UBE2D3, and RANGAP1) and energy production genes (XYLB, MTRF1 and ENOX1) that were associated with both conditions. Further analyses revealed that these shared genes were enriched in calcium signaling, long-term potentiation and neuroactive ligand-receptor interaction pathways that played a critical role in cognitive functions and neuronal plasticity.
doi:10.1038/srep25671
PMCID: PMC4862382  PMID: 27164557
24.  Age- and Sex-Specific Causal Effects of Adiposity on Cardiovascular Risk Factors 
Fall, Tove | Hägg, Sara | Ploner, Alexander | Mägi, Reedik | Fischer, Krista | Draisma, Harmen H.M. | Sarin, Antti-Pekka | Benyamin, Beben | Ladenvall, Claes | Åkerlund, Mikael | Kals, Mart | Esko, Tõnu | Nelson, Christopher P. | Kaakinen, Marika | Huikari, Ville | Mangino, Massimo | Meirhaeghe, Aline | Kristiansson, Kati | Nuotio, Marja-Liisa | Kobl, Michael | Grallert, Harald | Dehghan, Abbas | Kuningas, Maris | de Vries, Paul S. | de Bruijn, Renée F.A.G. | Willems, Sara M. | Heikkilä, Kauko | Silventoinen, Karri | Pietiläinen, Kirsi H. | Legry, Vanessa | Giedraitis, Vilmantas | Goumidi, Louisa | Syvänen, Ann-Christine | Strauch, Konstantin | Koenig, Wolfgang | Lichtner, Peter | Herder, Christian | Palotie, Aarno | Menni, Cristina | Uitterlinden, André G. | Kuulasmaa, Kari | Havulinna, Aki S. | Moreno, Luis A. | Gonzalez-Gross, Marcela | Evans, Alun | Tregouet, David-Alexandre | Yarnell, John W.G. | Virtamo, Jarmo | Ferrières, Jean | Veronesi, Giovanni | Perola, Markus | Arveiler, Dominique | Brambilla, Paolo | Lind, Lars | Kaprio, Jaakko | Hofman, Albert | Stricker, Bruno H. | van Duijn, Cornelia M. | Ikram, M. Arfan | Franco, Oscar H. | Cottel, Dominique | Dallongeville, Jean | Hall, Alistair S. | Jula, Antti | Tobin, Martin D. | Penninx, Brenda W. | Peters, Annette | Gieger, Christian | Samani, Nilesh J. | Montgomery, Grant W. | Whitfield, John B. | Martin, Nicholas G. | Groop, Leif | Spector, Tim D. | Magnusson, Patrik K. | Amouyel, Philippe | Boomsma, Dorret I. | Nilsson, Peter M. | Järvelin, Marjo-Riitta | Lyssenko, Valeriya | Metspalu, Andres | Strachan, David P. | Salomaa, Veikko | Ripatti, Samuli | Pedersen, Nancy L. | Prokopenko, Inga | McCarthy, Mark I. | Ingelsson, Erik
Diabetes  2015;64(5):1841-1852.
Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10−107) and stratified analyses (all P < 3.3 × 10−30). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.
doi:10.2337/db14-0988
PMCID: PMC4407863  PMID: 25712996
25.  A supportive family environment in childhood enhances the level and heritability of sense of coherence in early adulthood 
Purpose
To analyze the effects of genetic and environmental factors on sense of coherence (SOC) in young adulthood and whether family environment measured in childhood modifies these effects.
Methods
SOC was measured at 20–27 years of age in 3,193 Finnish twins using the Antonovsky’s 13-item short scale. The twins and their parents had rated their emotional family environment independently when the twins were 12 years of age. The data were analyzed using applications of structural linear equation modeling to twin data.
Results
Females rated SOC 2.42 points lower than males. Additive genetic factors explained 39 % of the variation of SOC in males and 49 % in females, whereas the rest of the variation was explained by environmental factors unique to each twin individual. For the dimensions of SOC, the highest genetic correlation was found between comprehensibility and manageability (0.90 in males and 0.97 in females). SOC was strongest in the participants who had reported supportive family atmosphere and low relational tensions to parents in childhood. These participants also had higher genetic variance and lower unique environmental variance of SOC when compared to those who reported emotionally more stressful family environment. The results were similar when we used parental rating of family environment.
Conclusion
Genetic factors are important for SOC, but genetic influences are much greater in supportive family environments. This emphasizes the importance of childhood home for the development of strong SOC.
doi:10.1007/s00127-014-0851-y
PMCID: PMC4844883  PMID: 24619310
Childhood environment; Gene–environment interactions; Genetic factors; Sense of coherence

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